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Biomedical subjects

Vincent M Lynch

Publications and source records attributed to Vincent M Lynch.

12 recordsLinked to original sources
PubMed2003

A novel and selective 5-HT2 receptor agonist with ocular hypotensive activity: (S)-(+)-1-(2-aminopropyl)-8,9-dihydropyrano[3,2-e]indole.

Serotonin 5-HT2 receptor agonists have recently been shown to be effective in lowering intraocular pressure in nonhuman primates and represent a potential new class of antiglaucoma agents. As part of an effort to identify new selective agonists at this receptor, we have found that (S)-(+)-1-(2-aminopropyl)-8,9-dihydropyrano[3,2-e]indole (AL-37350A, 11) has high affinity and selectivity (>1000-fold) for the 5-HT(2) receptor relative to other 5-HT receptors. More specifically, 11 is a potent agonist at the 5-HT2A receptor (EC50 = 28.6 nM, E(max) = 103%) that is comparable to serotonin. Evaluation of 11 in conscious ocular hypertensive cynomolgus monkeys showed this compound to be efficacious in reducing intraocular pressure (13.1 mmHg, -37%). Thus, 11 is a potent full agonist with selectivity for the 5-HT2 receptor and is anticipated to serve as a useful tool in exploring the role of the 5-HT2 receptor and its effector system in controlling intraocular pressure.

Administration, Topical↗
PubMed2003

Single side strapping: a new approach to fine tuning the anion recognition properties of calix[4]pyrroles.

Three calix[4]pyrroles bearing m-orcinol-derived diether straps of different lengths on one side of the tetrapyrrolic core have been synthesized and characterized. Structural information for an analogous diester bridged strapped system reported previously (Yoon, D. W.; Hwang, H.; Lee, C. H. Angew. Chem., Int. Ed. Engl. 2002, 41, 1757-1759) is also provided as are bromide and chloride anion affinities for all four systems determined by Isothermal Titration Calorimetry (ITC) in acetonitrile. Although both sets of the strapped calix[4]pyrroles displayed enhanced affinities for chloride and bromide anion, differences were seen among the various receptors that support the conclusion that the anion binding ability of calixpyrrole-type systems can be effectively tuned by modifying the length and nature of the bridging straps. In the specific case of the diether systems, the largest chloride affinity was seen with the shortest strap, whereas the largest affinity for bromide anion was recorded in the case of the longest strap. On the basis of these findings, as well as supporting (1)H NMR spectroscopic studies, it is postulated that not only cavity size per se, but also the ability of the aryl portion of the strap to serve as a CH hydrogen bond donor site are important in regulating the observed anion affinities.

Anions↗
PubMed2002

Trinuclear copper(II) complex showing high selectivity for the hydrolysis of 2'-5' over 3'-5' for UpU and 3'-5' over 2'-5' for ApA ribonucleotides.

The cooperative action of multiple Cu(II) nuclear centers is shown to be effective and selective in the hydrolysis of 2'-5' and 3'-5' ribonucleotides. Reported herein is the specific catalysis by two trinuclear Cu(II) complexes of L3A and L3B. Pseudo first-order kinetic studies reveal that the L3A trinuclear Cu(II) complex effects hydrolysis of Up(2'-5')U with a rate constant of 28 x 10(-)(4) min(-)(1) and Up(3'-5')U with a rate constant of 0.5 x 10(-)(4) min(-)(1). The hydrolyses of Ap(3'-5')A and Ap(2'-5')A proceed with rate constants of 24 x 10(-)(4) min(-)(1) and 0.5 x 10(-)(4) min(-)(1) respectively. The L3A trinuclear Cu(II) complex demonstrates high specificity for Up(2'-5')U and Ap(3'-5')A. Similar studies with the more rigid L3B trinuclear Cu(II) complex shows no selectivity and yields lower rate constants for hydrolysis. The selectivity observed with the L3A ligand is attributed to the geometry of the ligand-bound diribonucleotide which ultimately dictates the proximity of the attacking hydroxyl and the phosphoester to a Cu(II) center for activation and subsequent hydrolysis.

Adenine Nucleotides↗
PubMed2002

Quinoxaline-bridged porphyrinoids.

Quinoxaline-bridged porphyrinoids (3), the first macrocycles containing dipyrrolylquinoxaline (DPQ, 1) subunits, were synthesized from the condensation of the diformyl-substituted DPQ derivatives (2) and 1,8-diaminoanthracene. The resulting structures were confirmed by X-ray analyses, which showed encapsulation of CHCl(3) molecules within the columnar channels established by the stacked arrangement of the individual macrocycles. The solution phase interactions with fluoride and dihydrogenphosphate anions were studied in the case of the unsubstituted system 3a in CH(2)Cl(2). The binding affinities for these anions, studied at the tetrabutylammonium salts, were found to be enhanced relative to those of the simple, unsubstituted monomeric DPQ "parent" system (1a), presumably as the result of the combined effects of preorganization and cooperative binding permitted by the pyrrole NH donor groups. Positive homotropic allosteric anion binding was observed and is ascribed to the structurally coupled nature of the two binding cavities present in the macrocycles. Support for this latter contention came from energy minimization studies.

Anions↗
PubMed2002

Metal complexes of porphycene, corrphycene, and hemiporphycene: stability and coordination chemistry.

Porphyrin (P), porphycene (Pc), corrphycene (Cn), and hemiporphycene (Hpc) represent a series of well defined "4-N in" constitutional porphyrin isomers. These isomers, in the form of their octaethyl derivatives, represent a congruent set of porphyrinoids whose properties can be compared. In this study we report how variations in electronic structure and nitrogen-core size in the free-base forms of these four systems are reflected in the properties of their corresponding metal complexes. Specifically, the effects that these differences have on the axial ligation properties of the Zn(II), Mg(II), Ni(II), and Co(II) complexes of P, Pc, Cn, and Hpc in toluene using pyridine as the axial ligand are detailed. Also reported are the relative stabilities of these complexes under acidic conditions. It is shown that for the zinc, magnesium, and cobalt complexes, there are distinct differences in the ability to maintain four-, five-, or six-coordinate geometries in the presence of similar concentrations of pyridine. By contrast, no apparent differences in axial ligand binding affinity are seen for the four nickel complexes. Little difference in stability was likewise seen when these same complexes were subject to acid-mediated demetallation, with all four falling into stability class II, according to the accepted porphyrin stability ranking system. High stabilities were also seen in the case of the cobalt complexes, with the Pc and Cn complexes being of stability class III and the P and Hpc derivatives falling into stability class II. The Zn(II) and Mg(II) complexes were all far less stable than the corresponding Ni(II) and Co(II) complexes. In this case, semiquantitative analyses of the rate of acid-induced decomposition revealed the following stability sequence P>Cn>Hpc>Pc for both the Zn(II) and Mg(II) complexes. Single-crystal X-ray diffraction structures were solved for the Zn(II), Mg(II), and Ni(II) complexes of the octaethyl derivatives of Hpc, Cn, and Pc as well as a Co(II) octamethylcorrphycene and are reported as part of this study. These solid-state structures confirm four-coordinate species for the Ni(II) complexes, four- and five-coordinate species for the Mg(II) and Zn(II) complexes, and a six-coordinate species for the lone Co(II) complex.

Binding Sites↗
PubMed2002

Novel C3-symmetric molecular scaffolds with potential facial differentiation.

The conversion of 1,3,5-substituted benzene and mesitylene by electrophilic aromatic substitution and Sonogashira cross-coupling, respectively, furnished the C3-symmetric, hexasubstituted benzene derivatives 1 and 2 with an alternating substitution pattern. Based on the molecular scaffolds obtained, the two systems serve as model compounds for novel receptor molecules with distinct geometric features. X-ray structures have been obtained for 1 and 2, which are discussed in regard to their aptitude as receptor platforms or supramolecular building blocks. By looking at the rotational barriers for the functional groups placed around the molecular scaffolds by variable temperature 1H NMR spectroscopy, 1 and 2 turn out to exist in rapidly interconverting conformations. The alignment of these potential binding groups around the molecular scaffolds should be strongly biased by specific interactions with suitable guest molecules.

Journal Article↗
PubMed2002

Recurrence of carboxylic acid-pyridine supramolecular synthon in the crystal structures of some pyrazinecarboxylic acids.

X-ray crystal structures of pyrazinic acid 1 and isomeric methylpyrazine carboxylic acids 2-4 are analyzed to examine the occurrence of carboxylic acid-pyridine supramolecular synthon V in these heterocyclic acids. Synthon V, assembled by (carboxyl)O-H...N(pyridine) and (pyridine)C-H...O(carbonyl) hydrogen bonds, controls self-assembly in the crystal structures of pyridine and pyrazine monocarboxylic acids. The recurrence of acid-pyridine heterodimer V compared to the more common acid-acid homodimer I in the crystal structures of pyridine and pyrazine monocarboxylic acids is explained by energy computations in the RHF 6-31G* basis set. Both the O-H.N and the C-H...O hydrogen bonds in synthon V result from activated acidic donor and basic acceptor atoms in 1-4. Pyrazine 2,3- and 2,5-dicarboxylic acids 10 and 11 crystallize as dihydrates with a (carboxyl)O-H...O(water) hydrogen bond in synthon VII, a recurring pattern in the diacid structures. In summary, the carboxylic acid group forms an O-H...N hydrogen bond in pyrazine monocarboxylic acids and an O-H...O hydrogen bond in pyrazine dicarboxylic acids. This structural analysis correlates molecular features with supramolecular synthons in pyridine and pyrazine carboxylic acids for future crystal engineering strategies.

Journal Article↗
PubMed2002

Toward a stable hydroxyphosphorane.

[reaction: see text] Hydroxy-pentaoxy-phosphoranes are transient intermediates formed during the hydrolysis of various phosphoesters. Kinetic analyses support the existence of such compounds, although they are not isolated. In an attempt to create a stable example, 2 equiv of a ligand possessing a very high effective molarity were attached to a central phosphorus. Instead of obtaining a hydroxyphosphorane, analysis by (31)P and (19)F NMR spectroscopy and X-ray crystallography showed the product to be a phosphotriester. The reason for this is discussed.

Crystallography, X-Ray↗